AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Rheumatoid arthritis (RA) is a systemic, chronic, autoimmune inflammatory disease that affects the joints of women of all age groups. Pregnancy results in an altered immune state, which contributes to a change in the course of autoimmune illness. For decades, the ameliorating effects of pregnancy have been observed on disease activity in women with RA. Recent retrospective and prospective studies have confirmed this improvement in the disease activity of RA. Although 70-80% of patients enter remission during pregnancy, approximately a quarter of patients continue to have active disease or even worsening of the disease, requiring treatment through pregnancy. The improvement in arthritis during pregnancy tends to be short-lived, and most patients who improve relapse in the postpartum period. The effect of pregnancy on extra-articular manifestations of RA is not known.

Pathophysiology

The pathophysiology of this improvement in disease activity during pregnancy remains unknown. Various theories have been proposed to explain the ameliorating effect of pregnancy on RA. No single mechanism satisfactorily explains the improvement observed, and multiple factors are probably responsible for this decrease in disease severity.

Some of the proposed theories are as follows:

• The effect of hormonal changes during pregnancy (eg, increased cortisol, estrogen, and progestin levels)
• The effect of pregnancy on cell-mediated immunity (eg, decreased cell-mediated immunity, predominance of helper T cell 2 [TH2] cytokine profile)
• The effect of pregnancy on humoral immunity (eg, a proportional decrease in immunoglobulin G lacking terminal galactose units, the development of anti-HLA class II antibodies following exposure to fetal antigens, an elevated serum alpha-2 pregnancy-associated globulin [PAG] level)
• Altered neutrophil function during pregnancy (eg, decreased neutrophil respiratory burst)
• Elevated levels of anti-inflammatory cytokines, such as interleukin-1 receptor antagonist (IL-1Ra) and soluble tumor necrosis factor-a receptors (sTNFRs), and downregulation of Th1 cytokines during pregnancy
• The degree of HLA disparity between the mother and the fetus (the more genetically different mother and fetus are, the more likely that the RA will remit)

Possible causes for flare-up during the postpartum period include the following:

• A decrease in the anti-inflammatory steroid levels
• Elevated levels of prolactin (ie, proinflammatory hormone)
• Change in the neuroendocrine axis
• Change from a TH2 to a helper T cell 1 cytokine profile

Frequency

United States

RA is observed in 1-2% of the general population. Reproductive-aged women are affected; hence, pregnancy complicated by RA is not rare.

Mortality/Morbidity

• Effect of RA on pregnancy: Few studies address the effect of RA on pregnancy. Most women with RA have an uneventful course with no significant complications. Clinical experience suggests maternal morbidity during pregnancy and labor in patients with RA is comparable to that of women without RA. The literature contains some contradictory data in regard to rates of spontaneous abortions, preeclampsia, and preterm delivery among patient patients with RA.
• Effect of RA on fetal outcome: RA does not appear to adversely affect the fetal outcome. While a case-control study reported premature birth and growth reduction as possible effects of RA, other studies showed no adverse fetal outcomes in patients with RA who are pregnant. In general, no significant increase in maternal or fetal morbidity seems to be attributable to RA.
• Effect of RA on fertility: Patients with RA do not appear to have decreased fertility. However, they may experience a prolonged time to conception. Studies have reported that married women with RA have smaller families compared to women who do not have RA. Decreased sexual drive, pain, ovulation dysfunction, and an impaired hypothalamic-pituitary-adrenal axis may be responsible for these findings.

Sex

• RA affects women 2-3 times more commonly than men.

Age

• RA in pregnancy affects reproductive-aged women.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

History is targeted toward identifying the activity of rheumatoid arthritis (RA), complications related to pregnancy, and adverse effects of the various medications.

• Symptoms suggestive of RA disease activity
• • Constitutional symptoms may be present.
  • In most patients, morning stiffness and fatigue are diminished during pregnancy.
  • The likelihood of developing extra-articular manifestations of RA during pregnancy is not increased.
  • Regarding joint pain or stiffness, approximately 75% of patients notice improvement in their joint symptoms. Most of the patients who have a favorable response notice the decrease in pain as early as the first trimester and have persistent relief throughout their pregnancy. In some patients, this improvement occurs later, during the second or third trimester. Some patients achieve remission (16%). Patients experience a decrease in the number of joints involved and the severity of pain.
• Symptoms due to pregnancy
• • Nausea, vomiting, and morning sickness can occur during the first trimester. These symptoms may prevent absorption of medications.
  • Pedal edema and back pain that is unrelated to RA can occur in the later stages of pregnancy.

Physical

• Examination for RA disease activity and structural damage
• • Pallor may be present. Patients with RA can have anemia of chronic disease. Pregnancy could further lower the hematocrit value following volume expansion. Patients on nonsteroidal anti-inflammatory drugs (NSAIDs) can develop iron deficiency anemia from gastrointestinal blood loss.
  • Joint examination is performed to assess inflammatory activity and structural damage. Activity is assessed by the number of swollen, tender joints. The pattern of the joint involvement is the same as in the nonpregnant state (ie, involving small joints of the hands, wrists, shoulders, neck, knees, and ankles in a bilaterally symmetric pattern). The range of motion of hip and neck joints is assessed specifically because (1) patients may need to abduct and externally rotate their hips for vaginal delivery and (2) to identify patients with ligamental instability of the atlantoaxial joint.
  • Assess for extra-articular symptoms, including dry eyes, scleritis, dry mouth, pulmonary fibrosis, pleural effusion, and vasculitis.
• Examination to assess fetal growth and development and maternal health - Performed according to the obstetric protocol

Causes

• Women who notice improvement in RA disease activity during a previous pregnancy are more likely to have a favorable response during subsequent pregnancies.
• Patient age, RA disease duration, disease severity before pregnancy, and presence of rheumatoid factor do not help predict the outcome during pregnancy.
• Compared to women who did not improve, patients whose arthritis improved during pregnancy were more likely (odds ratio 9.7) to have maternal-fetal disparity in HLA class II antigens, especially for HLA DQ. They also had increased levels of pregnancy-related protein alpha-2 PAG.

WORKUP

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Laboratory blood tests are the same as for any pregnancy and include the following:
• • Hematocrit value to screen for anemia
  • Blood group to identify Rh-negative mothers
  • Rapid plasma reagent, hepatitis B, and HIV tests to identify diseases that can potentially affect the fetus
• The presence of rheumatoid factor does not help predict or correlate with the outcome of arthritis during pregnancy; therefore, assessing for rheumatoid factor is not required.
• The erythrocyte sedimentation rate cannot be used to assess rheumatoid arthritis (RA) disease activity during pregnancy because pregnancy alters the normal values.
• Because normocytic-normochromic anemia of chronic disease can occur in persons with RA, closer monitoring of hemoglobin values may be required. The volume expansion observed with pregnancy and the gastrointestinal blood loss associated with NSAID use can result in lower hematocrit values.
• If patients are on disease-modifying antirheumatic drugs (DMARDs), they need blood work to monitor for the adverse effects of the drugs. For sulfasalazine and NSAIDs, obtain a CBC count, an aspartate aminotransferase assay, and an alanine aminotransferase assay. For azathioprine, obtain a CBC count.

Imaging Studies

• Radiograph of the neck: In patients with persistent neck pain and neurological symptoms in whom ligamental instability is suggested, flexion and extension views of the neck are required.
• Ultrasound: This is performed to assess fetal well-being according to obstetric protocol.

TREATMENT

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Preconception counseling
• • Counseling patients about the teratogenicity and adverse effects of the medications used in treating rheumatoid arthritis (RA) before starting therapy is important. Patients may need a reminder about the importance of using contraception while on DMARDs, especially methotrexate, leflunomide, cyclophosphamide, cyclosporine, azathioprine, and gold injections.
  • Educate patients that because of a prolonged half-life, some of these medications may need to be discontinued several months before planned conception.
  • In addition to discontinuation, some patients who take DMARDs may require treatment with other medications to enhance their clearance.
• Drug information and recommendations
• • None of the medications used in the treatment of arthritis is absolutely safe during pregnancy. Hence, the decision to use medications should be made after careful assessment of the risks and benefits in consultation with the patient. Pain control through nonmedical management (eg, paraffin baths, decrease in physical activity, splinting, cold packs) is preferred. During the first trimester, most of the drugs should be avoided.
  • NSAIDs should be stopped at the beginning of a menstrual cycle when conception is planned, as NSAIDs have shown to interfere with blastocyst implantation in animal studies. Possible effects on the mother include prolonged gestation and labor, increased peripartum blood loss, and increased anemia. The potential adverse effects for the fetus include premature closure of the ductus arteriosus leading to fetal pulmonary hypertension, impaired fetal renal function with oligohydramnios, and increased cutaneous and intracranial bleeding. Stopping NSAID treatment 6-8 weeks before delivery is required to avoid adverse fetal effects. Short-acting NSAIDs (eg, ibuprofen, indomethacin, diclofenac) are preferred over long-acting agents. Experience with ketorolac, mefenamic acid, and nabumetone during pregnancy is limited.
  • Corticosteroids are potent anti-inflammatory agents. They are considered relatively safe in pregnancy when used in low doses (ie, <20 mg). However, they may increase the maternal risk of hypertension, edema, gestational diabetes, osteoporosis, premature rupture of membranes, and small-for-gestational-age babies. One meta-analysis found a 3.5-fold increase in risk of cleft palate in fetuses with first-trimester exposure.
  • • The choice of glucocorticoid depends on whether the mother or the fetus needs to be treated. Hydrocortisone and cortisone cross the placenta, but 11 beta-dehydrogenase, a placental enzyme, converts hydrocortisone to cortisone, which is biologically inactive; thus, the fetus is exposed to only approximately 10% of the maternal dose. Therefore, if steroid treatment is desired for the mother, hydrocortisone, cortisone, or prednisone should be chosen. Dexamethasone and betamethasone cross the placenta with similar maternal and fetal concentrations; thus, they are the treatment of choice for fetal respiratory distress.
    • The lowest possible steroid dose needed to control activity should be used in pregnancy. The routine use of oral calcium and vitamin D supplements is recommended. Stress doses of steroids should be used during labor and delivery if the mother received steroids (even low-dose) for more than 2-3 weeks during pregnancy, and the neonate should be monitored for evidence of adrenal insufficiency and infection.
  • Methotrexate is contraindicated in pregnancy because of its teratogenic effects. It is profoundly abortigenic and commonly used in the nonsurgical treatment of ectopic pregnancies. Teratogenic effects include craniofacial abnormalities, limb defects, and central nervous system defects such as anencephaly, hydrocephaly, and meningomyelopathy, especially with first trimester exposure. Because the active metabolites have a long half-life, methotrexate must be discontinued 3 months prior to conception; treatment with folic acid should be continued in that period and throughout pregnancy.
  • Leflunomide is extremely teratogenic and absolutely contraindicated in pregnancy. Its half-life is 14-15 days, but the active metabolite undergoes extensive enterohepatic circulation; thus, the drug takes up to 2 years to be undetectable in plasma. Therefore, discontinuation of the drug before conception is insufficient. The drug needs to be eliminated with administration of cholestyramine 8 g 3 times daily for 11 days. Plasma levels of less than 0.02 mg/L should be verified with 2 separate tests at least 2 weeks apart. If the levels are still not low enough, additional cholestyramine maybe given.
  • Azathioprine or gold injections can be used if the benefits outweigh the risks. Although fewer women who received azathioprine for renal transplant completed their pregnancies, no increase in fetal anomalies was observed. Azathioprine crosses the placenta, but the fetal liver lacks the enzyme inosinate pyrophosphorylase, which converts azathioprine to its active metabolite, 6-mercaptopurine; thus, the fetus is protected from the agent's teratogenic effects. In case series, the maternal use of azathioprine in pregnancy was associated with small-for-gestational-age infants, premature rupture of membranes, and intrauterine growth retardation. One case of pancytopenia, combined immunodeficiency, and craniofacial abnormalities was found. It is recommended for use in pregnant patients who require immunosuppression.
  • Anakinra, tumor necrosis factor-a (TNF-a) inhibitors and rituximab are the new successful biologic therapies being used in RA. At this time, limited data are available on their use in pregnancy. Few animal and human experiences with these medications are listed below. Although their use in pregnancy is currently not recommended, they might be the options for future use.
  • • In rats and rabbits, doses of up to 100 times the human dose of anakinra have not revealed evidence of impaired fertility or harm to the fetus.
    • Animal studies in pregnant mice have shown no evidence of maternal or embryo toxicity with use of an analogous monoclonal antibody that inhibited mouse TNF-a. In humans, one case report described a woman with Crohn disease who received infliximab before discovering she was pregnant. The woman delivered a premature baby with intracerebral and intrapulmonary bleeding who later died. This patient was also taking azathioprine, mesalamine, and metronidazole.
    • The infliximab (Remicade) safety database maintained by Centocor, Inc, reported a total of 133 pregnancies with direct exposure to infliximab. Their outcomes of live births, miscarriages, and therapeutic terminations were similar to that of the general US population. A recent online survey of US rheumatologists conducted in April 2005 relating to use of TNF inhibitors in RA found that, among 454 patients with RA who became pregnant while receiving biological therapy, 378 deliveries were normal, 9 babies were premature, 5 therapeutic abortions were performed, and 25 of the women miscarried.
    • Despite the above findings, these medications are recommended to be discontinued during pregnancy until further information on the safety of these drugs is available.
  • One case report has been described of a child born with transient granulocytopenia and lymphopenia following rituximab use in pregnancy. Because of the lack of sufficient data regarding its use, rituximab should be avoided in pregnancy at this time.
  • Discontinuing cyclosporine and cyclophosphamide 3 months prior to conception is recommended.
  • The preferred disease-modifying agents during pregnancy are sulfasalazine and hydroxychloroquine. No increase in fetal morbidity or mortality was observed following the use of sulfasalazine during pregnancy in patients with inflammatory bowel disease. Studies have not shown that sulfasalazine or sulfapyridine causes significant displacement of bilirubin from albumin.
  • • Hydroxychloroquine crosses placenta in humans and is observed in ocular tissues of mice. No real fetal toxicity was found at the dosages used for treatment of connective-tissue diseases (6.5 mg/kg) in clinical trials.
    • Hydroxychloroquine may be stopped in patients with RA as arthritis improves with pregnancy. Continuation of hydroxychloroquine administration through pregnancy is considered safer to keep well-controlled lupus stable rather than risking a flare-up in the peripartum period. Patients should be told of the potential risk of retinal toxicity to the fetus.

Surgical Care

• Patients with RA do not appear to have increased rates of cesarean delivery.
• Assisted delivery and cesarean delivery may be required in some cases.

Consultations

• Obstetrician and gynecologist: Work closely with the gynecologist, especially if patients are on disease-modifying agents or prednisone.
• Ophthalmologist: Patients on hydroxychloroquine may need an eye examination to assess for drug toxicity.

Diet

• A low-fat, high-carbohydrate diet with high-fiber content is recommended. Fish oils in moderate quantities can be taken during pregnancy.
• Over-the-counter herbal remedies are best avoided.
• Calcium supplementation is recommended to prevent osteoporosis.

Activity

• Strenuous activity is best avoided when patients have flare-ups of RA.
• Some people may notice worsening of their arthritis in cold weather; therefore, they may benefit from avoiding winter sports.

MEDICATION

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Nonsteroidal anti-inflammatory drugs

These agents have analgesic, antiinflammatory, and antipyretic activities. Their mechanism of action is unknown but may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may also exist, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.

Drug Category: Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Category: Disease-modifying antirheumatic agents

Potential benefit of use should outweigh risks. Slow onset of these agents must be considered before use during pregnancy. Effects can last for months, and decision to stop must be made before conception.

Drug Category: Biologic response modifiers

These newly engineered and specifically targeted biopharmaceutical agents target cellular subsets, adhesion molecules, T-cell receptors, class 2 major histocompatibility complex (MHC), and various cytokines.

Drug Category: Tumor necrosis factor-

TNF-a is a cytokine that plays a significant role in producing proinflammatory effects in RA. The biologic agents directed against TNF-a have been very successful in treating RA by decreasing inflammatory and immune responses.

FOLLOW-UP

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients may require admission for complications of labor and delivery.

Further Outpatient Care

• Patients must be monitored closely following delivery because most are likely to have arthritis flare-ups during the postpartum period.
• Breastfeeding may increase the likelihood of arthritis flare-up.

In/Out Patient Meds

• Patients can breastfeed, provided they are not on azathioprine, methotrexate, cyclophosphamide, or cyclosporine. Exercise caution if mothers are on sulfasalazine because this drug is secreted in the milk and adverse effects have been observed in an infant whose mother was a slow acetylator.
• Hydroxychloroquine is also secreted in breast milk; therefore, use this drug with caution. Hydroxychloroquine can potentially displace bilirubin and result in the development of kernicterus. The drug should be discontinued if the neonate has jaundice.
• Prednisone can be used safely during breastfeeding because small amounts (5% of the glucocorticoid dose) are secreted in breast milk. At doses higher than prednisone 20 mg once or twice daily, breast milk is recommended to be pumped and discarded 4 hours following the steroid dose to minimize drug exposure to the infant.
• NSAIDs can be used with caution, provided newborns do not have jaundice, because NSAIDs can displace bilirubin and predispose patients to the development of kernicterus.

Transfer

• Transfer may be required for surgical intervention.

Deterrence/Prevention

• Avoid pregnancy when rheumatoid arthritis (RA) is active, especially in the presence of extra-articular symptoms of vasculitis.
• Use contraception while taking DMARDs.

Complications

• Complications may occur due to the adverse effects of drugs on the fetus.

Prognosis

• The long-term effect of pregnancy in patients with RA is unknown. Retrospective studies suggest no significant adverse or positive effect of pregnancy on the course of RA.

Patient Education

• Patients with RA should be aware of the potential teratogenic effects of the drugs they are taking. Preconception counseling must be stressed.
• Use of contraception must be stressed frequently while patients are on teratogenic medications.
• When recommending treatment during pregnancy, patients must be informed of the potential adverse effects of the drugs on the fetus.
• For excellent patient education resources, visit eMedicine's Arthritis Center and Pregnancy and Reproduction Center. Also, see eMedicine's patient education articles Rheumatoid Arthritis, Understanding Rheumatoid Arthritis Medications, Birth Control Overview, and Birth Control FAQs.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to inform patients of teratogenic effects of certain DMARDS
• Failure to inform patients about the potential adverse effects of the drugs recommended during pregnancy on maternal and fetal health
• Failure to diagnose pregnancy before starting teratogenic disease-modifying agents
• Failure to inform patients to not breastfeed while on certain drugs (eg, azathioprine, cyclosporine, cyclophosphamide)

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Barrett JH, Brennan P, Fiddler M, Silman A. Breast-feeding and postpartum relapse in women with rheumatoid and inflammatory arthritis. Arthritis Rheum. May 2000;43(5):1010-5. [Medline].
• Bowden AP, Barrett JH, Fallow W, Silman AJ. Women with inflammatory polyarthritis have babies of lower birth weight. J Rheumatol. Feb 2001;28(2):355-9. [Medline].
• Brennan P, Barrett J, Fiddler M, et al. Maternal-fetal HLA incompatibility and the course of inflammatory arthritis during pregnancy. J Rheumatol. Dec 2000;27(12):2843-8. [Medline].
• Crocker IP, Baker PN, Fletcher J. Neutrophil function in pregnancy and rheumatoid arthritis. Ann Rheum Dis. Jul 2000;59(7):555-64. [Medline].
• Cush JJ. Biological drug use: US perspectives on indications and monitoring. Ann Rheum Dis. Nov 2005;64 Suppl 4:iv18-23. [Medline].
• Janssen NM, Genta MS. The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy, and lactation. Arch Intern Med. Mar 13 2000;160(5):610-9. [Medline].
• Jorgensen C, Sany J. Modulation of the immune response by the neuro-endocrine axis in rheumatoid arthritis. Clin Exp Rheumatol. Jul-Aug 1994;12(4):435-41. [Medline].
• Nelson JL, Hughes KA, Smith AG, et al. Maternal-fetal disparity in HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis. N Engl J Med. Aug 12 1993;329(7):466-71. [Medline].
• Nelson JL, Ostensen M. Pregnancy and rheumatoid arthritis. Rheum Dis Clin North Am. Feb 1997;23(1):195-212. [Medline].
• Ostensen M, Hartmann H, Salvesen K. Low dose weekly methotrexate in early pregnancy. A case series and review of the literature. J Rheumatol. Aug 2000;27(8):1872-5. [Medline].
• Ostensen M, Aune B, Husby G. Effect of pregnancy and hormonal changes on the activity of rheumatoid arthritis. Scand J Rheumatol. 1983;12(2):69-72. [Medline].
• Ostensen M, Forger F, Nelson JL. Pregnancy in patients with rheumatic disease: anti-inflammatory cytokines increase in pregnancy and decrease post partum. Ann Rheum Dis. Jun 2005;64(6):839-44. [Medline].
• Rudolph JE, Schweizer RT, Bartus SA. Pregnancy in renal transplant patients: a review. Transplantation. Jan 1979;27(1):26-9. [Medline].
• Russell AS, Johnston C, Chew C, Maksymowych WP. Evidence for reduced Th1 function in normal pregnancy: a hypothesis for the remission of rheumatoid arthritis. J Rheumatol. Jun 1997;24(6):1045-50. [Medline].
• Temprano KK, Bandlamudi R, Moore TL. Antirheumatic drugs in pregnancy and lactation. Semin Arthritis Rheum. Oct 2005;35(2):112-21. [Medline].
• Unger A, Kay A, Griffin AJ, Panayi GS. Disease activity and pregnancy associated alpha 2-glycoprotein in rheumatoid arthritis during pregnancy. Br Med J (Clin Res Ed). Mar 5 1983;286(6367):750-2. [Medline].

Article Last Updated: Nov 17, 2006